Oral Drug Delivery May 2011 Lo Res

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CONTENTS

The views and opinions expressed in this issue are those of the authors.

Due care has been used in producing this publication, but the publisher

makes no claim that it is free of error. Nor does the publisher acceptliability for the consequences of any decision or action taken

(or not taken) as a result of any information contained in this publication.

Front cover image: Multiple chrome pills, 3D4Medical.com/

Science Photo Library.

No Longer a Hit-or-Miss Proposition:

Once-Daily Formulation for Drugs with

pH-Dependent Solubility

Gopi Venkatesh, Director of R&D & Anthony Recupero,

Senior Director, Business Development

Aptalis Pharmaceutical Technologies 4-8

A possible approach for the desire to innovate

Brian Wang, CEO & Dr Junsang Park, CSO

GL PharmTech 10-13

COMPANY PROFILE -

Mayne Pharma International 14-15

From Powder to Pill: A Rational Approach to

Formulating for First-into-Man Studies

Dr Robert Harris, Director, Early Development

Molecular Profiles Ltd 16-19

LiquiTime* Oral Liquid Controlled Release

Camille Rivail, Business Development Analyst & Dr Jean

Chatellier, Vice-President, Alliance Management

Flamel Technologies SA 20-21

Formulation Flexibility Broadens the Scope

for Oral Thin Film Technology

Martha Sloboda, Business Manager

& Dr Scott Barnhart, Technical Director

ARx, LLC 22-24

Solumer Technology: a Viable Oral Dosage

Form Option for BCS Class II Molecules

Dr Robert Lee, Vice-President, Pharmaceutical

Development & Dr Amir Zalcenstein, CEO

SoluBest, Ltd 26-29

Controlled Drug Release: Novel Time-Delayed

Formulations and their Clinical Evaluation

Dr Carol Thomson, Chief Operating Officer

Drug Delivery International Ltd 30-32

Liquid-Fill Hard Two-Piece Capsules:

The Answer to Many Product Development Issues

Mr Gary Norman, Product Development Manager

Encap Drug Delivery 34-36

Multi-Tip Tooling: A Guide

Dale Natoli, Vice-President

Natoli Engineering Company, Inc 38

Oral Drug Delivery:

Formulation Selection Approaches

& Novel Delivery Technologies

This edition is one in the ONdrugDelivery series of pub-

lications from Frederick Furness Publishing. Each issuefocuses on a specific topic within the field of drug deliv-

ery, and is supported by industry leaders in that field.

EDITORIAL CALENDAR 2011:

June: Injectable Drug Delivery (Devices Focus)

July: Injectable Drug Delivery (Formulations Focus)

September: Prefilled Syringes

October: Oral Drug Delivery

November: Pulmonary & Nasal Drug Delivery (OINDP)

December: Delivering Biotherapeutics

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Oral Drug Delivery: Formulation Selection Approaches

& Novel Delivery Technologies is published by

Frederick Furness Publishing.

Copyright 2011 Frederick Furness Publishing.

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www.ondrugdelivery.com Copyright 2011 Frederick Furness Publishing4

MEDICATION ADHERENCE

It is estimated that 33-69% of all medication-

related hospital admissions in the US are due

to poor medication adherence, with a resultant

cost of approximately US$100 billion a year.1-6

Taking medications exactly as prescribed and

following appropriate lifestyle recommenda-

tions is highly beneficial and may reduce the

impact of side effects.

Practitioners should always assess adher-

ence to therapy and may improve adherence by

emphasising the value of a patients regimen,

making the regimen as simple as possible, and

customising the regimen to the patients life-

style.7 Simple dosing (one pill, once daily) can

help maximise adherence, particularly when

combined with reinforcing visits / messages

from healthcare practitioners, despite the fact

that 10-40% of patients on simple regimens

continue to have imperfect dosing adherence.8,9

WHY ARENT ONCE-DAILY ORAL

DOSAGE FORMS AVAILABLE FOR

ALL DRUGS?

As the orally administered pharmaceutical

dosage form passes through the human gastro-

intestinal (GI) tract, drug should be releasedfrom the dosage form and be available in solu-

tion at or near the optimal site for drug absorp-

tion to occur.10-12 The rate at which the drug is

released from a dosage form and goes into solu-

tion is important for the kinetics of drug absorp-

tion. The dosage form and hence the pharma-

ceutical ingredient (API) is subjected to varying

pH levels during GI transit.13-16 Specifically, pH

varies from a minimum of about 1.2 to a maxi-

mum of around 7.4 (stomach pH: 1.2-2.5, which

increases to 3.5-6.1 upon consumption of food;

bile pH: 7.0-7.4; pH 5.0-6.0 in small intestine;

and pH: 6 to 7 in the large intestine).

GI fluid volume and agitation can vary sig-

nificantly, which has substantial impact on drug

dissolution and absorption.17 Moreover, transit

time may vary significantly in individual parts

of the GI tract, depending on individual size and

prevailing local conditions.18

Truly once-daily dosage forms of many weak-

ly basic drugs are not commercially available.

Several attempts have been made in the past

at developing once-daily delivery systems of

weakly basic drugs, such as carvedilol, ondanse-

tron, and dipyridamole, with limited success.19-22

This is largely because the absorption of a weakly

basic drug is critically affected by its solubility

and the required total daily dose. The ability to

maintain these drugs in a soluble form as the drug

passes through the GI tract throughout the day has

been a substantial challenge for oral formulators.

SOLUBILITY ENHANCEMENT BYORGANIC ACIDS

The solubility-enhancing property of

organic acids23 is exploited during the manu-

In this article, Dr Gopi Venkatesh, Director of R&D, and Dr Anthony Recupero, Senior

Director, Business Development, both of Aptalis Pharmaceutical Technologies (formerly

Eurand), describe a specific application of Diffucaps technology, which allows the creation

of once-daily oral formulations of weakly basic active pharmaceutical ingredients, previously

extremely difficult to achieve, but with significant benefits to patient adherence.

NO LONGER A HIT-OR-MISS PROPOSITION:

ONCE-DAILY FORMULATION FOR DRUGSWITH PH-DEPENDENT SOLUBILITY

Anthony Recupero, PhD

Senior Director, BusinessDevelopmentT: +1 267 759 9346E: [email protected]

Aptalis Pharmaceutical

Technologies

790 Township Line RoadSuite 250

Yardley, PA 19067United States

www.AptalisPharmaceutical

Technologies.com

Gopi Venkatesh, PhD

Director of R&D


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Copyright 2011 Frederick Furness Publishing www.ondrugdelivery.com

facture of customised-release (CR) dosage

forms using Diffucaps technology. The

potential for in situ formation of acid addition

compounds24 is averted by using a sustained-

release (SR) coating membrane between the

inner organic acid layer and the weakly basic

drug layer. The SR-coating membrane thus

applied, precisely controls the release of the

organic acid ensuring drug is not retained in

the dosage form for lack of solubilising acid

in theDiffucaps formulation.

DIFFUCAPS TECHNOLOGY

Diffucaps technology in its simplistic

form (see Schematic of the Time Pulsatile

Release / Time Sustained Release (TPR/TSR)

bead shown in Figure 1) involves the prepara-

tion of:

(1) drug-containing cores by drug-layering on

inert particles

(2) customised release (CR) beads by coating

immediate release (IR) particles with one or

more functional dissolution rate controlling

polymers or waxes

(3) combining one or more functional polymer

coated Diffucaps bead populations into

hard gelatin or hydroxypropyl methylcel-

lulose (HPMC) capsules.24

MECHANISM OF DRUG RELEASE

FROM TPR/TSR BEADS

The water-insoluble and enteric polymers

are dissolved in a common solvent mixture

and the solution is sprayed onto drug particles.These two polymers may exist as molecularly

dispersed or as molecular clusters in the lag-

time coating membrane applied on the drug

cores (Figure 1).

During dissolution testing in two-stage dis-

solution media (first two-hour dissolution test-

ing in 700 mL of 0.1N HCl and thereafter

testing in 900 mL of pH 6.8 buffer obtained

by adding 200 mL pH modifier) or upon oral

administration, water or body fluid is blocked

from imbibing into the core as the polymeric

system is impermeable in the acidic medium

or gastric fluid. When the pH of the medium

is changed to 6.8 or following exit from the

stomach, the penetrating dissolution medium or

intestinal fluid selectively dissolves the enteric

polymer molecules or molecular clusters start-

ing from the outermost membrane layer, thereby

creating tortuous nanopore channels for dis-

solved drug to pass through.23

The tortuosity increases with increasing

coating thickness and/or decreasing enteric

polymer content, and consequently, the drug

release from the TPR beads having no barrier

coat becomes sustained with increasing thick-

ness of the TPR coating.

DEVELOPMENT OF ONCE-DAILY

DOSAGE FORMS OF WEAKLY

BASIC DRUGS

Below is shown the method for the prepara-

tion25 of CR drug delivery systems comprising

one or more IR, SR, TPR/TSR, Delayed-Release

(DR) bead populations, themselves containing

a weakly basic, nitrogen moiety-containing API

such as ondansetron, carvedilol, dypiramidole,

lamotrigine or iloperidone, which is moderately

soluble at pH 6, and at least one pharmaceutically accept-

able organic acid as a solubiliser (see the schemat-

ics of SR organic acid bead & TPR/TSR bead

containing a weakly basic drug shown in Figure 2).

The method comprises the following steps:

a) layering an organic acid on 25-30 mesh sugar

spheres;

b) applying an SR coating on acid-layered beads

with a water-insoluble polymer to control the

rate of release of the acid;

5

Figure 1: Diffucaps Customised Drug Release Bead (A) soaked in pH 1.2 or resident in the stomach and (B) soaked in pH 6.8 orin transit in the intestinal tract.

Figure 2: Diffucaps: Customised Drug Release Bead for pH-sensitive Drugs(e.g. Ondansetron HCl).


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c) preparing IR beads by layering the weakly

basic nitrogen moiety-containing API and

applying a protective seal-coat with a water-

soluble polymer;

d) preparing SR beads by applying a barrier

(SR) coating of a water-insoluble polymer

on the IR beads to sustain the drug release

over several hours (if needed);

e) preparing TPR beads by applying a lag-time

coating on IR beads or SR beads (called

TSR beads) comprising water-insoluble and

enterosoluble polymers for a weight gain

sufficient to achieve a lag time (a time period

of less than 10% drug release) of 2-6 hours

followed by a sustained-release profile; and

f) filling into a capsule a mixture of IR beads

and one or more TPR bead populations at

appropriate amounts to achieve a target phar-

macokinetics profile suitable for a once-daily

dosing regimen.

The following examples demonstrate how

Aptalis Pharmaceutical Technologies utilised

the above process to formulate once-daily dos-

age forms of ondansetron and iloperidone.

NAUSEA AND VOMITING

FOLLOWING CHEMOTHERAPY,

RADIATION THERAPY, OR SURGERY

Radiotherapy-induced nausea and vomit-

ing (RINV), chemotherapy-induced nausea and

vomiting (CINV), and postoperative nausea and

vomiting (PONV) remain the most common anddistressing challenges facing patients receiving

these cancer therapies or following surgical pro-

cedures under general anaesthesia (occurring in

up to 80% of cases).25-33

Nausea and vomiting very often occur together

but can also occur independently. RINV and

CINV during cancer therapy can have a direct

and significant impact on adherence to primary

therapy. Some of the most highly prescribed anti-

emetics suffer from a short-half life requiring mul-

tiple daily doses for control of emesis. Between

doses, the plasma levels of the anti-emetic can

drop well below efficacious levels increasing

the risk for breakthrough nausea and vomiting,

particularly when subsequent doses are not taken

exactly as scheduled. Proper control of acute and

breakthrough nausea and vomiting therefore can

be achieved with a higher probability and a higher

level of confidence with a customised-release

(CR) dosage form for oral administration, prefer-

ably administered prior to the procedure.

Weakly basic ondansetron HCl dihydrate

Ondansetron HCl dihydrate, the API in the

branded product, Zofran Tablets (4 and 8 mg

base equivalent) and Zofran Oral Solution,

marketed by GlaxoSmithKline, is a selective

serotonin 5-HT3

blocking agent (an antiemetic).

The API in Zofran ODTs (orally disintegrating

tablets, 4 and 8 mg) is ondansetron base. All

products are immediate release (IR) formulations.

Ondansetron is indicated for the prevention of

nausea and vomiting associated with radiotherapy

(adults: 8 mg tid) and/or chemotherapy (adults:

8 mg bid to tid) and prevention of postoperative

nausea and/or vomiting (adults: 8 mg bid).

Ondansetron is a weakly basic drug having a

pKa of 7.4 and an elimination half-life averag-ing approximately 3.81 hours. It is practically

insoluble in the pH environment of the intestinal

tract. However, there is a dramatic increase

in solubility in aqueous organic acid solution,

making it a good candidate for developing once-

daily dosage forms based on the organic acid

approach ofDiffucaps technology.

Modified release (MR), once-daily dosage

forms of ondansetron HCl dihydrate using

Diffucaps technology

Pharmacokinetic/biopharmaceutical modeling

and simulation of possible plasma profiles based

on available pharmacokinetic data as a guide

in the design of customised-release (CR) dos-

age forms in order to be suitable for a once-

daily dosing regimen is typically performed using

WinNonlin and/or GastroPlus computer simu-

lation and modeling techniques. The CR capsule

product was designed to comprise appropriate

amounts of both IR and TPR components wherein

the TPR component used SR-coated organic acid

beads as inert cores to design multiple TPR beadpopulations with different lag times.33 The use

of such methods resulted in reduced feasibility

development time and enhanced the probability

of success of the program.

For the IR component of the formulation,

rapid release (RR) granules comprising ondan-

setron, mannitol, and organic acid were devel-

oped, which are designed to release the drug

faster than, or similar to,Zofran IR tablets even

under alkaline pH conditions.33

Ondansetron HCl CR capsules were

designed to comprise appropriate amounts of

both RR granules and TPR beads. Three CR

formulations were prepared for pharmacokinetic

(PK) testing in healthy volunteers.33

A randomised, four-way crossover pilot PK

study was conducted that included 12 healthy

male volunteers, aged 18-55 years, with a wash-

out period of seven days. Each volunteer was

dosed with one of three test formulations of

Ondansetron MR at 0800h, or two Zofran (8

mg) at 0800h and 1630h after an overnight fast.

Figure 3 shows the mean plasma concentration-

time profiles achieved. The relative bioavail-

ability compared with 8 mg IR bid reference

was approximately 0.85 for all test formulations

(Test Formula 1, 2, and 3) at the end of 24 hours.

Based on these results, Test Formula 3, given

the product code EUR1025, was advanced into

pivotal PK studies which have been completed.34

In these trials, single and repeated oral adminis-

trations of 24 mg EUR1025 resulted in similar

rate and extent of exposure as 8 mg Zofran tid.

Steady-state concentrations of Treatment 2 (8 mg

Zofran bid) and Treatment 3 (8 mgZofran tid)

are equivalent to that of single administrations of

two and three 8 mg Zofran

, respectively.34

Thetotal exposure of ondansetron (AUC

0-24) from

EUR1025 on day six was approximately 13%

higher than that observed on day one, suggesting

minor accumulation following repeated dosing.

Figure 3: Pilot PK Study - Ondansetron QD versus Ondansetron IR (Zofran).


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Copyright 2011 Frederick Furness Publishing www.ondrugdelivery.com 7

The total exposure of Treatment 1 (24 mg

EUR 1025) appears to be nearly equivalent to

that of Treatment 3 (8 mgZofran tid) at steady

state. The product is now ready to enter Phase III

clinical development.34

ILOPERIDONE TPR BEADS AND

RELEASE PROFILES

The Diffucaps organic acid approach used

with ondansetron is applicable to any weakly

basic drug, which is at least slightly soluble at a

pH3, but is poorly soluble or practically insolu-

ble above pH 6. Iloperidone, the API in Fanapt,

is a weakly basic, dopamine and serotonin recep-

tor antagonist exhibiting antipsychotic activities.

Iloperidone (12 mg) is dosed twice daily.

The incidence of adverse effects in

patients treated with Fanapt 20-24 mg/daywere twice that occurring in patients treated

with Fanapt 10-16 mg/day indicating an MR,

once-daily formulation may improve the side

effect profiles of iloperidone. Initial studies

indicate that by combining IR and TPR bead

populations at appropriate quantities (as deter-

mined by simulation and modeling) to provide

desired in vitro release profiles, it would be

possible to achieve target plasma profiles suit-

able for a once-daily dosing regimen.

ADVANTAGES OF CR DIFFUCAPS

DRUG DELIVERY SYSTEMS

Controlled-release drug delivery systems

consisting of coated multiparticulates, particu-

larly based on Diffucaps technology, which

typically have a particle size in the range of 200-

600 m, exhibit characteristic target in vitro

profiles, as well as target plasma concentration-

time profiles to be suitable for a once-daily

dosing regimen.

Multiparticulate drug delivery systems, such

as Diffucaps, offer the following advantages

over conventional controlled-release monolithic

dosage forms such as matrix or coated tablets

including osmotic delivery systems:

Dispersed along the GI Tract for more effec-

tive delivery

Predictable and consistent GI transit time

thereby minimising food effect

Low probability of dose dumping

Reduced inter- and intra-subjectvariability

Easy adjustment of multiple dose strengths

In addition, the Diffucaps technology offers

incremental advantages: Easy adjustment of target plasma profiles

including combining bead populations exhibit-

ing differing release profiles

Ability to create combination products of

incompatible actives or actives requiring dif-

fering target plasma profiles

Capability to create micro-environments:

Create a sustainable acidic pH micro-envi-

ronment within coated bead to solubilise

the weakly basic drug (which is practically

insoluble at pH 6.0 or above) in order to

extend its release into the GI tract

Create a sustainable alkaline pH micro-

environment within coated bead to moder-

ate the solubility of a weakly basic drug

(which is extremely soluble in the entire

physiologically relevant pH range of 1.0 to

8.0) to avoid dose dumping

Improve patient adherence due to reduced fre-

quency of dosing, ease of oral administration,

reduction in incidence of adverse events, and/

or improved safety profile

Additional product patent protection

CONCLUSIONS

Adherence to oral medication regimens,

and therefore effective therapy, is a common

issue for patients across multiple indications.

Although simple dosing regimens (one pill,

once daily) as provided by extended release

(ER) formulations for a number of products

are available, there are still many drugs for

which an ER, once-daily form has proven to

be exceptionally challenging to develop. These

challenging molecules frequently have water

solubility issues which may also be complicated

by limited molecule half-life.

The Diffucaps technology is one approach

that effectively overcomes such challenges,

allowing for straightforward development of

ER, once-daily formulations that help to improve

adherence, which can result in improved effi-

cacy and patient quality of life.

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How did you feel when you heard your brand

product was easily copied by a generic company

after the expiration of its new chemical entity

patent? And what about the case when someone

from sales & marketing came and complained

of setbacks in developing a pre-defined refor-

mulation product?...

For various reasons, with which readers

will already be familiar, individuals working

in pharmaceutical product development and

formulation have been under significant pres-

sure for some time. This pressure may have

made possible various kinds of open-innovation

by prompting the adoption of technologies or

products from outside.

The drug delivery industry has been work-

ing as an innovator and excellent partner over

the past 30 years, providing technologies that

have enabled brand pharmaceutical compa-

nies to take new steps. This is surely one rea-

son why the number of reformulated productsreached about triple that of new chemical

entities (NCEs) in 2009 (75 versus 26).1 As

a player in the oral drug delivery field, we at

GL PharmTech were pleased to note that oral

drug delivery products captured about 10% of

the top 200 product sales, which reportedly

reached US$14.5 billion.

UNDER PRESSURE FOR

REFORMULATION

As product developers using oral drug deliv-

ery technology, GL PharmTech is constantly

considering what gaps innovators want to fill in

their currently marketed products. What should

be the factor to drive reformulation?

There are many reasons why currently mar-

keted products could be reformulated. These

can originate from aspects of marketing, manu-

facturing, regulation, generic competition, and

even sometimes a purely scien-

tific basis. These various rea-

sons can come alone, together,

or complicatedly combined.

Therefore, a single outside

technology or reformulated

product could not fill all the gaps

or cover possible voids the inno-

vator did not feel compelled to

address at one time. This might

be the driving force for why

innovative pharma companies

have their departments of devel-

opment review outside technology as often as

possible and compile it in their databases.

Whenever we imagine someone at an inno-

vator company trying to align all the variables

to find a fit for their molecules or productswith outside drug delivery technologies, the

picture gives a strong feeling that a new drug

delivery player might be what is required to

make every thing click together.

Here, Hunsik (Brian) Wang, Chief Executive Officer, and Junsang Park, PhD, Chief ScientificOfficer, both of GL PharmTech, introduce GLARS, a novel concept extended-release triple-

layered tablet delivery technology for delivery to the intestine and colon.

A POSSIBLE APPROACH FOR THE DESIRETO INNOVATE

Hunsik (Brian) Wang

Chief Executive OfficerT: +82 31 739 5220 (Ext. 102)F: +82 31 739 5034E: [email protected]

Dr Junsang Park

Chief Scientific OfficerT: +82 31 739 5220 (extension 301)F: +82 31 739 5220E: [email protected]

GL PharmTech138-6 Sangdaewon JungwonSeongnamRepublic of Korea (South Korea)

HOW DID YOU FEEL

WHEN YOU HEARD YOUR BRAND

PRODUCT WAS EASILY COPIED

BY A GENERIC COMPANY AFTER

THE EXPIRATION OF ITS NEW

CHEMICAL ENTITY PATENT?


11/40


NEEDS FOR MEETING A NEW

CONCEPT IN ORAL EXTENDED

RELEASE

This situation could be particularly true in

the field of oral extended-release dosage forms.

The first big successes OROS from Alza(now Johnson & Johnson, New Brunswick,

NJ, US) and Geomatrix from Skyepharma

(London, UK) had a large impact in the field

of oral extended-release drug delivery technol-

ogy. However, there has not since been a other

strong player showing a comparable, remark-

able success, and the platform patents of both

technologies have expired. In addition, the rela-

tively short gastro-intestinal transit time cannot

expectedly or unexpectedly give a new start

to blockbuster products, even by applying the

already-existing technologies. In other words,

the molecule candidates on the market or under

development must have a suitable half-life for

those technologies to be applied.

Recently, a novel oral extended release tech-

nology was presented. Astellas Pharma (Tokyo,

Japan; formerly Yamanouchi Pharma) suggest-

ed a possible cause for limited absorption in the

colon and developed a new dosage form capable

of dragging and retaining gastro-intestinal fluid

into the dosage form itself, which could, in turn,

act as drug-releasing media in the colon.3, 4

They found another main reason for mal-

absorption in the colon to be that there was

no additional surrounding fluid present for

active substance in dosage form to be released

from, and described how this limitation could

be overcome to some degree by incorporating

highly water-retaining polymers into the dosage

form. They named this technology OCAS (Oral

Controlled Absorption System).

Up until now, Astellas has applied this tech-

nology to at least two products, according to the

literature, including tamsulosin, a global lead-

ing drug for anti-benign prostatic hyperplasia

(BPH), and mirabegron, an anti-incontinencedrug. The reformulated tamsulosin product has

been on sale in European regions under various

local brand names such as Alna OCAS, Omnic

OCAS, Flomaxtra XL, Urolosin OCAS and

Praf T. Mirabegron has been in Phase III clini-

cal trials in various countries.

The reformulated OCAS tamsulosin product

was reported to show not only higher night-time

maintenance of plasma concentrations during

but also no food effects upon its pharmacoki-

netic profiles.5, 6

GLARS: A NOVEL INTESTINAL AND

COLONIC EXTENDEND-RELEASE

TECHNOLOGY

The focus of GL PharmTech over the past

ten years has been on developing a technol-

ogy named GLARS (Geometrically Long

Absorption Regulated System). The system

entraps more gastro-intestinal fluid into the dos-

age form at early dissolution time to give further

extended absorption in the colon.

We have now reached a remarkable milestone.

During the course of our work, we fabricated a

triple-layered tablet, where the drug and very

hydrophilic excipients are incorporated into the

middle layer while highly water-retaining and

swellable materials are embedded in the upper

and lower layers (see Figure 1).

After oral administration, the surrounding

GI fluid can penetrate very quickly into the

middle layer, thus the upper and lower layers

concurrently swell rapidly. These rapidly swol-

len upper and lower layers enclose the lateral

side of the middle layer in quick-time (as shown

in Figure 2).

The amount of water drawn into the tablet

reaches about 3-5 times the weight of the tablet

itself and it can function, in turn, as additionalmedia which enables further later drug release out

of the dosage form when it passes into the colon.7

The key feature of GLARS is the middle

layer, where it horizontally divides the tablet

structure. As long as the surrounding water

penetrates into the tablet core, it can perform its

role to diffuse outward from the core. During

the diffusion process the water can also move

upwards and downwards, and this additional

diffusion, together with the diffusion of GI fluid

present outside the tablet, allows the upper and

lower layers to be quickly swollen and gelled,

at the same time.

As is already recognised in the field, a

conventional matrix sustained-release tablet

has its own erosion, diffusion, swelling front,

and un-swollen intact core. Achieving com-

plete swelling of a tablet without an intact

core before considerable erosion during normal

gastro-intestinal transit time has appeared to be

challenging. From this standpoint the insertion

of a highly water-penetrating middle layer into

GLARS was a radical approach.

Another feature of this system is rapid

enclosing of the tablets lateral side with the

upper and lower layers in a relatively short time.

As shown in Figure 3, after closing, drug release

is mainly demonstrated through the enclosed

lateral side, where the orange colour (from the

incorporated colourant) in the middle layer is

much thicker than on the other sides.

PROOF OF CONCEPT

Tamsulosin

The first target for determining whether this

system could actually operate was the block-

buster molecule, tamsulosin.8 Marketed under

the name Harnal, as well as Flomax, this

product was originally formulated into enteric-matrix granules in a hard gelatin capsule. In

Asia, including Japan and Korea, a normal

dose is 0.2 mg, compared with 0.4 mg in the

Americas and Europe.

Figure 1: Triple-layered structure ofGLARS

Figure 2: Morphological changes in GLARS upon water contact


12/40


As presented in Figure 4, Tamsulosin

GLARS, including a double amount of the API

(0.4mg), showed a nearly similar peak con-

centration to Harnal containing only 0.2 mg

of the API. Nonetheless, the extent of absorp-

tion, AUC, was not reduced but, instead, nearly

doubled.

When considering normal cases of most

types of drug product with dose proportionality

the greater the dose administered, the propor-

tionally higher the pharmacokinetic parameters

Cmax

and AUC. However, the GLARS system

demonstrated a proportionally higher extent of

absorption without a remarkable increase in the

rate of absorption. This result suggests that the

system can be applied to types of drugs with

the very close relationship of peak concentra-

tion versus adverse effects, for which extended

release dosage forms are desired.

Another finding in the application was that

the therapeutic concentration was persistent

even during the night. Considering reports that

nocturia is a key worry frequently raised by

BPH patients, longer duration of action at night

could be a very meaningful step for meeting

patients ongoing needs.9

The relatively rigid swollen matrix structure

of GLARS formulations allows drug release to

be unaffected by surrounding mechanical flux,

which can provide relatively consistent in vivo

drug release irrespective of the degree of gastro-

intestinal motility.

Tianeptine

Another proof on concept study was car-

ried out with tianeptine, an anti-depressant,

developed and marketed under the name

Stablon by Servier (Neuilly-sur-Seine,

France). The purpose of the application was

to determine whether the system could reduce

the number of daily administrations for better

patient compliance.

Figure 5 represents the results of the pharma-

cokinetic study, where the total amount of the

API was the same, 37.5 mg. In terms of the phar-

macokinetic parameters, no large difference was

shown between Tianeptine GLARS (GX-2903)

once daily, and three-times-daily administration

of the immediate-release dosage form.

Of course, this should be further evaluated

to determine whether this kind of plasma profile

is clinically effective and comparable with theperformance of existing immediate-release dos-

age forms.

CREATING EARLY PARTNERSHIPS

Several oral drug delivery technologies have

come and gone, and new systems still emerge

even today. However, their fates appear to be

very similar to those of NCEs. Approximately

five years is needed to demonstrate any phar-

maceutical or clinical evidence of one technol-

ogy. In addition, reformulated products must be

exclusively marketed for at least ten years.

Then, we, as drug delivery industry workers,

have only five years between showing evidence

and launching a product into market.

Another aspect to be considered is that

there comes a time when additional innovative

pharmaceutical applications are needed over the

previously much-used simple matrix-type sus-

tained release form. When exclusivity expires,

there is the likely tendency of copying by

generic companies in a very short time.

Considering both aspects in combination,

the marriage of the NCE with the drug delivery

system, through a partnership between pharma

company and drug delivery company, should be

created as early as possible.

Early partnering would represent a great step

towards securing more valuable next-generation

reformulated products.

REFERENCES:

1. Rekhi GS. Advances in solid dose oral

drug delivery. ONdrugDelivery: Oral drug

Delivery & Advanced Excipients, 2010, 14-18.2. Bossart J .Oral drug delivery:

the numbers behind the business.

ONdrugDelivery: Oral drug Delivery &

Advanced Excipients, 2010, 4-6.

Figure 4: Pharmacokinetic profiles of Tamsulosin GLARS, which shows doubled extentof absorption without a dose-proportional increase of peak concentration

Product Cmax (ng/mL) AUCt (hr ng/mL

Harnal (0.2mg; qd) 5.160.97 69.622.3

GLPTs GLARS (0.4mg; qd 6.602.70 114.3439.9

Figure 3: Schematic representation of rapid water penetration through middle layer aswell as swelling and enclosing of upper and lower layers


13/40


3. Sako K et al. Influence of physical fac-

tors in gastrointestinal tract on acetami-

nophen release from controlled-release

tablets in fasted dogs. Proceedings of

the 6th Conference of the Academy of

Pharmaceutical Science and Technology,

Japan. 1990, 30-31.

4. Sako K et al. Relationship between gela-

tion rate of control-release acetaminophen

tablets containing polyethylene oxide and

colonic drug release in dogs. Pharm Res,

1996, 13(4), 594-598.

5. Michel MC et al. The pharmacokinetic pro-

file of Tamsulosin oral controlled absorption

system(OCAS). Eur. Urol. Suppl. 2005,

4, 15-24

6. Djavan B et al. The impact of Tamsulosin

oral controlled absorption system(OCAS)

on nocturia and the quality of sleep: pre-

liminary results of a pilot study. Eur Urol

Suppl, 2005, 4, 61-68.

7. Park JS et al. A novel three-layered tab-

let for extended release with various layer

formulations and in vitro release profiles.

Drug Devel Ind Pharm, 2011, 37 (in press).

8. Park JS et al. Formulation variation and

in vitro-in vivo correlation for a rapidlyswellable three-layered tablet of Tamsulosin

HCl. Chem Pharm Bull, 2011, 59 (in

press).

9. Schulman CC et al. The impact of noc-

turia on health status and quality of

life in patients with lower urinary tract

symptoms suggestive of benign prostatic

hyperplasia(LUTS/BPH). Eur Urol Suppl,

2005, 4, 1-8.

13

Figure 5: Pharmacokinetic profiles of Tianeptine GLARS, which shows the possibility ofonce daily administration

Product Cmax (ng/mL) AUCt (hr ng/mL

Stablon (12.5mg x tid) 335107.6 2705.3601.8

GLPTs GLARS (37.5mg qd 359.274.2 2849.7622.9

ONdrugDelivery is now fi rmly established worldwide.

It is the leading sponsored themed drug delivery publication.

www.ondrugdelivery.com

WEKNOWDRUG DELIVERYWant to KNOWdrug delivery too?Just subscribe FREE to ONdrugDelivery online today!


14/40

14 www.ondrugdelivery.com Copyright 2011 Frederick Furness Publishing

A leading pharmaceutical organisation built

on a heritage of 160 years of industry excel-

lence, Mayne Pharma International is a

market-driven company offering a range of

drug delivery technologies. Mayne Pharma

International offers contract development

and commercial manufacture for oral andtopical pharmaceutical products.

Mayne Pharma International has comprehen-

sive experience in the solid oral Drug Delivery

System (DDS) market, encompassing develop-

ment and manufacture of these products.

The company has:

more than 30 years experience in suc-

cessfully developing DDS products for the

global market a dedicated product development facility

which meets cGMP standards, and includes

pilot-scale plant equipment; this allows a

scale-up pathway from small clinical trial

batches to full commercial manufacture

proven ability to develop and successfully

transfer manufactured product and technol-

ogy to other sites around the world

intellectual property and formulation

capabilities to help with product life cycle

management.

Mayne Pharma International has been grant-

ed, or applied for, patents that protect its vari-

ous drug delivery technologies. The in-market

sales of products developed at the Salisbury,

Australia facility using its technologies are in

excess of US$500 million per year.

Mayne Pharmas drug delivery systems

include:

Technology to control drug release

To enable pulsed release, extended release,

and delayed release profiles (pellet/bead

formulations produced using extrusion and

marumerisation, or spheronisation processes,

see below). Pellets may be tabletted or encap-

sulated. This technology is very flexible andit can be adapted to the specific formulation

needs of a particular drug substance.

Technology to improve oral bioavailability

Particularly for insoluble drugs (SUBA

technology, see below).

Technology to taste mask liquids and tablets

To improve palatability and aid swallowing

(Cleantaste technology, see below).

TECHNOLOGY TO CONTROL

DRUG RELEASE

Pellet (or bead) technology allows a vari-

ety of different drug delivery profiles to be

achieved by coating drug and excipient with

various polymers. The drug cores are gener-

ally spheroidal in shape and have a diameter

in the range of 300-1,700 m. Pellets can be

presented in capsule or tablet dosage forms.

Two types of process are used to generate

the spheroidal particles (see diagram):

The first of these processes, which allows

drug potencies up to 90%, utilises extru-

sion and marumerisation to form a drug

core with a polymer coat.

The second process is known as spheroni-

sation, where the drug particles are fixed to

the outside of a seed core (typically a sugar

sphere). This process provides a very tight

size distribution of pellets. Drug potencies

up to 60% are possible.

For both of the processes above, the desired

drug release profile is achieved by coating

these particles with an appropriate polymer.

Mayne Pharma International has particular

expertise in polymer selection and process-

ing. The company can also work with a widerange of solvent systems.

SUBA

SUBATM is a novel technology for enhanc-

ing the bioavailability of poorly water solu-

ble drugs utilising a solid dispersion of drug

in various polymers.

SUBATM has been shown to double the

oral bioavailability of itraconazole when

compared with the innovator product(Sporanox).

CLEANTASTE

Cleantaste technology allows a polymer

coat to be applied to very small particles

(25-150 m diameter) to improve taste. It

is also possible to use this technology to

improve stability or to deliver sustained

release characteristics. The fine, non-gritty

texture of product produced by this tech-

nology lends itself to being used in orally

dispersible tablet and liquid formulations, as

well as encapsulated products. Cleantaste

acetaminophen and ambroxol have been

commercialised and launched in Australia,

the US and Japan.

SERVICES SUMMARY

Mayne Pharma International can develop and

manufacture oral and topical formulations for

clinical trials and commercial supply. Mayne

Pharma International can provide:

Tablets (immediate, extended, delayed or

pulsed release and taste masked)

Capsules (powder, pellets (beads)

Liquids and Creams

COMPANY PROFILE - MAYNE PHARMA INTERNATIONAL

Pellet technology used for controlled release formulations.


15/40

15Copyright 2011 Frederick Furness Publishing www.ondrugdelivery.com

Placebo formulations can be provided to

match client specifications or innovator

product. Packaging and labelling can be

completed to customer requirements.

In addition to its drug delivery technologies,

Mayne Pharma International offers a number

of specialty services:

Formulation Development

Provide solutions to a range of common

formulation challenges such as poor solubil-

ity, poor bioavailability, short half life, low

Cmax, poor powder flow, non-uniform crys-tal size and scale-up issues.

ABOUT MAYNE PHARMA

A leading pharmaceutical organisation

built on a heritage of 160 years of

industry excellence, Mayne Pharma

International is a market-driven company

offering a range of drug delivery technolo-

gies. Mayne Pharma International offers

contract development and manufacturing

company for oral and topical pharmaceuti-

cal products.

Mayne Pharma international competes in

the oral drug delivery, branded, generic and

value-added API markets. The oral pharma-

ceutical business at Salisbury, Australia, is a

GMP facility.

Annual production capacity:

2,500 million capsules and tablets

100 tonnes of bulk product

16 million units of liquids and creams

The site is approved by all major regulatory

authorities:

FDA: United States

MHRA: UK

TGA: Australia

TPD: Canada

Mayne Pharma International has generated

numerous patents in the drug delivery field.

9 patent families

48 registered patents

14 pending applications

Mayne Pharma International is located at

Salisbury (Adelaide), South Australia. There

is 12,000 m2 of manufacturing space on a

19-hectare site. Mayne Pharma International

is a wholly owned subsidiary of Mayne

Pharma Group Ltd, an Australian public

company listed on the ASX.

Mayne Pharma International

PO Box 700SalisburySouth Australia 5108Australia

T: +61 8 8209 2604F: +61 8 8281 6998E: [email protected]

www.maynepharma.com


16/40


A new experimental drug substance shows

great promise from pre-clinical studies for the

treatment of a disease which afflicts millions of

patients worldwide. What is the best strategy for

testing the drug in man for the first time? This

is a question that all companies developing new

drugs face on a regular basis.

Entering Phase I clinical trials is a key

milestone in any drug development project and

to reach this stage as quickly as possible is of

paramount importance especially for those

with limited budgets. Of equal importance is to

ensure that the new drug substance is adminis-

tered in a form that will give it the best chance

of success in early clinical assessment. A poor

choice of formulation strategy can lead to poor

clinical data which can lead to re-formulation

and a prolonged Phase I clinical programme, or

even termination of the project.

So how do you decide what is the best for-

mulation for a new drug, assuming at this stage

that it is intended for oral administration?

KNOW YOUR DRUG SUBSTANCE

From preclinical studies, there should be

sufficient information to be able to define the

drug according to its water-solubility and per-meability characteristics in accordance with the

biopharmaceutics classification system (BCS).1

Also, Lipinskis Rule of Five 2 is a useful tool

in predicting the oral bioavailability of drug

molecules based on certain molecular attributes.

The BCS has proved a useful tool to formu-

lators for classifying drug substances, but its

primary purpose is for establishing criteria for

biowaivers, and alternative developability clas-

sification systems have recently been proposed.3,4

How well a drug is absorbed into the blood-

stream from the gastro-intestinal tract (GIT) is

governed predominantly by (i) drug solubility in

the gastric and intestinal fluids and (ii) perme-

ability through cell lipid bilayers. BCS Class I

drugs are freely soluble in GIT fluids and perme-

ate easily through lipid bilayers. These drugs are

well absorbed when given orally and present the

easiest task when choosing a formulation strat-

egy. BCS Class IV drugs on the other hand are

defined as poorly soluble (in GIT fluids) and per-

meate poorly across lipid bilayers. Consequently,

these drugs exhibit poor oral bioavailability and

pose the formulator the greatest challenge.

Additional physicochemical and biological fac-

tors which can challenge formulators are:

Drug instability:

during processing or in the formulation (e.g.

apomorphine)

in the GIT (e.g. when drug is acid labile, as

with omeprazole). Narrow absorption window in the intestine

(e.g. acyclovir, captopril).

Drug metabolism and/or efflux within the

intestinal wall (e.g. cyclosporin A).

Making the right choice of formulation for the first-into-human studies of a product candidate

is extremely important and has significant time and cost implications for the development

programme. Here, Robert Harris, PhD, Director, Early Development at Molecular Profiles,

describes various formulation options available and suggests methods that can be used to select

the best formulation option for a new orally delivered drug substance.

FROM POWDER TO PILL:

A RATIONAL APPROACH TO FORMULATINGFOR FIRST-INTO-MAN STUDIES

Dr Robert Harris

Director, Early DevelopmentT: +44 115 871 8883F: +44 115 871 8889E: [email protected]

Molecular Profiles Ltd

8 Orchard PlaceNottingham Business Park

NottinghamNG8 6PXUnited Kingdom

www.molprofiles.com


17/40


Drug absorption and metabolism can vary

between animal species and therefore it is notalways possible to predict the influence of bio-

logical factors (e.g. pre-systemic metabolism)

on drug uptake in humans from preclinical

animal studies.

DECIDE ON A FORMULATION

STRATEGY

For first-into-human studies it is usual to

administer the drug either as powder-in-bottle

(for reconstitution prior to administration) or in

capsules, which offer the greatest flexibility for

dose adjustment. Choosing a formulation will

depend on the properties of the drug substance

and the target dose. Decision trees can be very

effective tools in helping select the most appro-

priate formulation strategy.5,6 Figure 1 is an

example of a decision tree which can be used to

select a suitable formulation strategy for first-

into-human clinical trials.

The simplest formulation strategy is not to

formulate just administer the drug substance

with no additional excipients. In this case the

required quantity of drug active is added directly

to a container (for reconstitution with a suitable

liquid prior to ingestion) or to a capsule. This

approach is widely used within the industry as

it significantly reduces the time and cost for

progressing to first-into-man studies. For small

quantities of units the active is weighed into

each capsule or bottle by hand. For large quanti-

ties of capsules or where the required dose is

< 10 mg, capsule filling can be achieved accu-

rately by use of specialised precision powder

dosing equipment (for example, Xcelodose

(Capsugel, Peapack, NJ, US), as shown in

Figure 2).The drug-in-capsule/bottle approach is par-

ticularly suited for BCS Class I compounds,

which are absorbed easily from the GIT.

Although there are obvious benefits in adopt-

ing a drug-in-capsule/bottle approach, it should

be considered with caution if the compound isnot BCS Class I. If a drug substance does not

wet easily or if its solubility in water is poor the

drug may be poorly absorbed from the GIT and

hence exhibit poor bioavailability. If there is a

known history of poor or variable absorption in

animal models then a formulation strategy to

enhance water-solubility of the drug substance

should be considered.

Two basic principles for enhancing water-

solubility of the drug substance are (i) reduction

of the particle size of the drug substance and (ii)

use of solubility-enhancing vehicles.

Brief descriptions of typical solubility-

enhancing formulation strategies are given

below. Regardless of the formulation strategy

chosen, it is vital to assess drug solubility fol-

lowing dilution of the test formulations in

aqueous media. The dissolution test procedures

used should simulate both gastric and intestinal

conditions (in terms of pH, fluid volume, etc).

Particle size reduction

Increasing the overall surface area of a solidcan lead to more rapid dissolution of the drug sub-

stance. Micronising equipment (e.g. fluid energy

mills) can reduce particle size down to 2-10

m. Taking the principle of size reduction even

further, there are now technologies available to

produce submicron nanocrystals through pre-

cipitation (bottom up) or wet milling (top down)

techniques.7,8 Following particle size reduction

the drug substance can be dispensed into capsules,

either as drug alone or as a powder blend (with

excipients), depending on the required dose and

flow properties of the milled drug substance.

Solubility-enhancing vehicles

For each of the strategies described below

the resulting formulation can be filled into

capsule shells for administration. Capsule fill-

ing machines which are suitable for this pur-

pose include the IN-CAP (Dott. Bonapace,

Limbiate, Italy), suitable for powders or liq-

uids/semi-solids, and the CFS 1200 (Capsugel)

which is suitable for liquids/semi-solids.

Solution/semi-solid capsule formulations:

If the drug can be dissolved in a suitable

pharmaceutically acceptable vehicle then it may

be appropriate to consider preparation of a solu-

tion of the drug which can be filled into cap-

sules. The main benefit of this approach is that

pre-dissolving the compound overcomes the

initial rate limiting step of particulate dissolu-

tion in the aqueous environment within the GIT.

However, a potential problem is that the

drug may precipitate out of solution when

the formulation disperses in the GIT, par-

ticularly if the solvent is miscible with water

(e.g. polyethylene glycol). If the drug is suf-ficiently lipophilic to dissolve in a lipid vehicle

there is less potential for precipitation on dilu-

tion in the GIT, as partitioning kinetics will

favour the drug remaining in the lipid drop-

Figure 1: Formulation strategy decision tree for first-into-human studies.

Figure 2: Xcelodose precision powderdispenser.


18/40


lets. Also, lipidic vehicles are generally well

absorbed from the GIT and in many cases this

approach alone can significantly improve the

oral bioavailability 9,10 compared with admin-

istration of the solid drug substance, but there

may be significant inter and intra-subject vari-

ation in drug uptake, depending on the capac-

ity of individuals to digest these lipid-based

formulations.

In recent years there have been significant

advances in the use of lipidic excipients and sur-

factants to produce self-emulsifying drug deliv-

ery systems (SEDDS) and self-micro-emulsi-

fying drug delivery systems (SMEDDS) for

oral drug delivery.11 These formulations form

emulsions or micro-emulsions spontaneously

on contact with aqueous media. Both SEDDS

and SMEDDS use pharmaceutically acceptable

surfactant excipients to achieve self-emulsifica-

tion, therefore eliminating the reliance on the

gastro-intestinal secretions (such as bile salts) to

emulsify the lipids in the formulation.

Solid solutions

Solid solutions12

(also sometimes describedas solid dispersions) are molecular dispersions

of the drug molecules in a polymer matrix. This

approach combines two principles to enhance

water solubility of a drug:

1. Conversion of the drug material into its amor-

phous state generally, a drug substance is

easier to dissolve when in the amorphous

state compared with the crystalline state, due

to absence of ordered intermolecular bonds

2.Incorporation of the amorphous drug sub-

stance in a hydrophilic polymeric matrix a

number of hydrophilic, polymeric materi-

als have been used as solubility-enhancing

matrices for drug substances. For example,

polyvinyl pyrrolidone (PVP) and polyethyl-

ene glycol (PEG 6000) have been used for

preparing solid solutions containing poorly

soluble drugs.

Solid solutions can be prepared by dis-

solving both the drug compound and the

polymer in a suitable volatile solvent. On

removing the solvent (e.g. by spray drying)

an amorphous drug-polymer complex is pro-

duced. On cooling, the drug is then trapped in

an amorphous state within the water-soluble

polymer matrix, thus enhancing the water-

solubility of the drug.

One potential problem with this type offormulation is that the drug may favour a more

thermodynamically stable crystalline state,

which can result in the drug compound crys-

tallising in the polymer matrix. Therefore the

physical stability of such formulations needs

to be assessed using techniques such as differ-

ential scanning calorimetry (DSC) and X-ray

crystallography.

For formulations in which the drug is to be

dissolved (in liquid or solid vehicles) miscibil-

ity of the drug substance with the vehicle is

a key requirement to maximise water-solu-

bility of the drug and to maintain the physical

stability of the formulation (i.e. prevent drug

precipitation). A comparison of the solubility

parameters for drug and excipients can be used

to predict miscibility of the drug the excipi-

ents.13,14,15 The closer together the solubility

parameters are between drug and excipient the

higher the probability of the drug and excipi-

ent being miscible. An example of how this

information can be used to gauge miscibility

of drug with excipients is illustrated in Figure3. The graph shows that the polymer with the

closest spatial proximity to acetaminophen is

HPMC and we would therefore expect there

to be a high probability that the drug will be

miscible in this polymer.

SOLID DISPERSIONS

Solid dispersions are similar to solid solu-

tion formulations, except that the drug exists in

the form of discrete particles dispersed within a

polymer or wax matrix.

MELT EXTRUSION

This technique 16,17 is an extension of the

solid solution approach described previously.

It consists of extruding a co-melt of the drug

substance and a polymer through a heated screw

to produce a solid extrudate which can then be

milled to produce granules (for encapsulation

or compression into tablets). As with the solid

solution approach, the production of a melt

extruded drug/polymer matrix is an effective

method of increasing the water solubility of a

poorly water-soluble drug substance. The effec-

tiveness of this approach depends on miscibility

of drug and polymer substances and on the drug

substance and the polymer exhibiting similar

melting points.

MELT GRANULATION

With this approach a water soluble polymer

is used as a binding agent in a powder mixture

to produce a granule blend. The blend is heated

to a temperature at which the polymer bind-ing agent softens (without completely melting)

which results in formation of aggregates com-

prised of the drug and excipients. The granule

mass is then cooled, sieved and is then suitable

Figure 3: Comparison of acetaminophen and polymer excipients according to theirHansen partial solubility parameters.

PVP= polyvinyl pyrrolidone PEG= polyethylene glycol EC= ethyl celluloseHEC= hydroxyethyl cellulose PEO= polyethylene oxide HPMC= hydroxypropylmethyl cellulose


19/40


for either encapsulation or compression into tab-

lets. This technique has proved to be effective in

enhancing water-solubility of several drugs.18,19

INCLUSION COMPLEXES SUCH AS

CYCLODEXTRINS

Cyclodextrins 20 are doughnut-shaped mole-

cules with a lipophilic surface on the inside ring

and a hydrophilic surface on the outer surface

of the ring. The principle behind this strategy is

that the poorly soluble drug molecule fits into

the inner ring and the outer hydrophilic surface

of the cyclodextrin holds the complex in solu-

tion. The inclusion complex can be prepared

by dissolving the drug and cyclodextrin in a

common solvent or by solid-state mixing of the

materials using a high-attrition technique, such

as ball milling.

CONCLUSION

In conclusion, a number of factors need to

be taken into consideration in deciding how

best to take a new drug entity into first-into-man

studies. The drug-in-capsule approach is often

seen as a cost effective and time saving option

for testing a drug in Phase I studies. Indeed, it

significantly reduces the complexity of early

stage development and progression from drug

substance to a Phase I clinical trial can be

achieved within weeks. However, if the drug

substance has known solubility/bioavailability

limitations (as is the case for more than 40% of

NCEs) then due consideration should be given

to formulation strategies which can enhance

drug solubility in the GIT.

Developing a suitable drug formulation

for first-into-human studies can be prob-

lematic and time consuming, especially for

poorly water-soluble drugs. By predicting

drug-excipient miscibility (through compari-

son of solubility parameters) and subsequently

using a decision tree approach for choosing an

appropriate formulation strategy, it is possible

to eliminate a significant proportion of trial

and error from a drug formulation develop-

ment project. This rational approach to formu-

lation development offers obvious advantages

in reducing time for project completion and

maximising the effectiveness of formulations

for Phase I studies.

REFERENCES

1. FDA Guidance for Industry. Waiver of in

vivo bioavailability and bioequivalence stud-

ies for immediate-release solid oral dosage

forms based on a biopharmaceutics classifi-

cation system. (August, 2000).

2. Lipinski, CA et al. Experimental and com-

putational approaches to estimate solubility

and permeability in drug discovery and

development settings. Adv. Drug Deliv.

Rev. (1997), 23: 3-25.

3. Wu, CY & Benet, LZ. Predicting drug dis-position via application of BCS: transport/

absorption/elimination interplay and devel-

opment of a biopharmaceutics drug disposi-

tion classification system. Pharm. Res.

(2005), 22: 11-23.

4. Butler, JM and Dressman, JB. The devel-

opability classification system: application

of biopharmaceutics concepts to formulation

development. J. Pharm. Sci. (2010), 99:

4940-4954.

5. Brachu. S, et al. A decision-support tool

for the formulation of orally active, poorly

soluble compounds. Eur. J. Pharm. Sci.

(2007), 32: 128-139.

6. Hariharan, M, et al. Reducing the time to

develop and manufacture formulations for

first oral dose in humans. Pharm. Tech.,

October 2003, 68-84.

7. Kesisoglou, F, et al. Nanosizing Oral

formulation development and biopharma-

ceutical evaluation. Adv. Drug Deliv. Rev.

(2007), 59: 631644.

8. Eerdenbrugh, BV, et al. Top-down produc-

tion of drug nanocrystals: Nanosuspension

stabilisation, miniturization and transforma-

tion into solid products. Int. J. Pharm.

(2008), 364: 64-75.

9. Hauss, DJ. Oral lipid-based formulations.

Adv. Drug Deliv. Rev. (2007), 59: 667676.

10. ODriscoll, CM & Griffin, BT.

Biopharmaceutical challenges associated

with drugs with low aqueous solubility

the potential impact of lipid-based formula-

tions. Adv. Drug Deliv. Rev. (2008), 60:

617624.

11. Pouton, CW & Porter, CJH. Formulation

of lipid-based delivery systems for oral

administration: Materials, methods and

strategies. Adv. Drug Deliv. Rev. (2008),

60: 625637.

12. Vasconcelos, T, et al. Solid dispersions as

strategy to improve oral bioavailability of

poor water soluble drugs. Drug Discovery

Today (2007), 12: 1068-1075.

13. Greenhalgh, DJ, et al. Solubility param-

eters as predictors of miscibility in solid

dispersions. J. Pharm. Sci. (1999), 88:1182-1190.

14. Adamska, K, et al. Selection of solubility

parameters for characterization of phar-

maceutical excipients. J. Chromatogr. A

(2007), 1171: 90-97.

15. Albers, J, et al. Evaluation of predictive

models for stable solid solution formation.

J. Pharm. Sci. (2011): 100: 667-680.

16. Crowley, MM, et al. Pharmaceutical

applications of hot-melt extrusion: Part

1. Drug. Dev. Ind. Pharm. (2007), 33:

909-926

17. Repka, MA, et al. Pharmaceutical appli-

cations of hot-melt extrusion: Part 2.

Drug. Dev. Ind. Pharm. (2007), 33: 1043-

1057

18. Yang, D, et al. Effect of the melt granula-

tion technique on the dissolution charac-

teristics of griseofulvin. Int. J. Pharm.

(2007), 329: 72-80.

19. Passerini, N, et al. Preparation and char-

acterisation of ibuprofenpoloxamer 188

granules obtained by melt granulation.

Eur. J. Pharm. Sci., (2002), 15: 7178.

20. Brewster, ME & Loftsson, T.

Cyclodextrins as pharmaceutical solubi-

lizers. Adv. Drug Deliv. Rev., (2007), 59:

645666.

IN WHICH EDITION

COMPANY APPEAR?WWW.ONDRUGDELIVERY.COM

COULD YOUR


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Paediatric and geriatric drug delivery are major

challenges in drug development: it is estimated

that 50% of the population have difficulties in

swallowing solid oral dosage forms. This is espe-

cially true among children under 12 years and the

elderly; there is a real need for age-adapted for-

mulations to promote better treatment compliance.

Indeed, patients have been found to break

tablets into fragments in order to facilitate

administration or to adapt the dose, generating

major risks such as inaccurate dosing, or stabil-

ity issues of the residual fragments.

Liquid formulations are thus one of the most

appropriate dosage forms for these subpopula-

tions, as they allow better compliance compared

with classic tablets or capsules as well as better

dose adaptability (age- and weight-dependent).

However, a number of challenges are related

to the use of liquid formulations:

The palatability or taste of the solution, which

must be sufficiently agreeable in flavour to be

consumed. With respect to bitter-tasting drugs,

adding sweeteners and flavors to mask the

taste is often not sufficient.

A lack of enteric or modified drug delivery tech-

nologies as compared with tablets and capsules.

Stability issues of drugs in liquid form.

LiquiTime, Flamel Technologies innovative

delivery platform, meets these different challenges.

Based on a multi-microparticles approach,

LiquiTime allows stable, controlled-release, ready-

to-use liquid oral suspensions, with good mouth

feel, of one or several combined drugs over time.

The microparticles (shown in Figure 1)

are composed of a drug core coated with a

proprietary multifunctional diffusion film. The

expertise developed by Flamel in coating in

fluidised beds allows accurate and reproducible

coating on very small drug cores to manufacture

microparticles with narrow size distribution and

final particle diameters below 200 m.

The microparticles size and the narrow

distribution optimise mouth-feel, generating a

smooth, liquid formulation with the possibility

to adjust the flavour using aroma agents. The

encapsulation of the active within the micropar-

ticles allows taste-masking, even for the most

unpleasant-tasting drugs.

LiquiTime enables tailoring and accurate fit-

ting of any release profile, especially zero-order

kinetics, to optimise pharmacokinetics (Figure 2)

for a wide range of therapeutic applications and

drugs (unlike ion exchange resin-complex tech-

nology, which is limited solely to ionic drugs).

Other benefits may also be obtained, suchas the possibility to mix immediate-release and

extended-release kinetics for fast onset and

extended release, or the possibility of mixing

different drugs with different release kinetics.

The multiparticulate nature of the dosage form

minimises inter- and intra-individual variation as

compared with conventional tablets or capsules.

In this article, Camille Rivail, Business Development Analyst, and Jean Chatellier, PhD, Vice-President, Alliance Management, both of Flamel

Technologies, describe the companys LiquiTime technology, which enables liquid formulations that are palatable, can incorporate variousmodified-release profiles, and are stable with long shelf-lives. The technology meets the need for liquid oral formulations in the large and growing

number of patients who have difficulty swallowing conventional tablets and capsules, including the young and the elderly.

LIQUITIME* ORAL LIQUID CONTROLLEDRELEASE DRUG DELIVERY PLATFORM

Dr Jean Chatellier

Vice-President, AllianceManagement

Flamel Technologies SA

33 avenue du Dr Georges Levy69693 Vnissieux CedexFrance

T: +33 472 783 434

F: +33 472 783 446E: [email protected]

www.flamel.com

Camille Rivail

Business Development Analyst

200m

Figure 1 : Flamel TechnologiesLiquiTime-based coated microparticleshave an average diameter


21/40


Regarding stability, one of the main techni-

cal hurdles related to liquid forms is to maintain

the performance of the drug over time to pro-

vide an acceptable shelf-life. Due to its unique

approach, LiquiTime has demonstrated long-

term physical and performance stability of over

24 months of storage.

The physical properties of LiquiTime, such as

viscosity, density, have been optimised to ensure

precise and reproducible sampling to be delivered

with existing marketed dosing devices (for exam-

ple, plastic syringes), allowing flexible and accu-

rate dose titration adapted to individual patients.

Development time of LiquiTime formulations

has been optimised through the use of cutting-edge

equipment and the skill and experience of the

Flamel development team. Beyond the lab, cGMP

manufacturing of clinical trial material and scale-

up to commercial size can be rapidly executed atFlamels US FDA-approved industrial plant.

LiquiTime is protected by a strong IP portfo-

lio, including several granted patents in territo-

ries including the US, EU and Japan.

KEY BENEFITS OF LIQUITIME

Easy to swallow, good mouth feeling, taste

masked

Liquid formulations stable over 24 months

Applicable to a wide range of drugs, not lim-

ited to ionic drugs as with resin-complex based

technology

Zero-order kinetics

Combination of immediate-release and extend-

ed-release kinetics possible

Combination in the same formulation of differ-

ent drugs with different release kinetics possible

Use GRAS materials to warrant safety

Rapid development time under cGMP conditions

Ease to scale-up to industrial scale

Clinical Proof of Concept achieved in humans

for a liquid suspension of an undisclosed drug

for treatment of children

Broad and strong IP protection

ABOUT FLAMEL TECHNOLOGIES

Flamel Technologies SA (NASDAQ: FLML)

is a leading drug delivery company focused on the

goal of developing safer, more efficacious formu-

lations of drugs that address unmet medical needs.

Flamel Technologies has collaborations

with a number of leading pharmaceutical and

biotechnology companies, including Baxter,

GlaxoSmithKline (Coreg CR, carvedilol phos-

phate), Merck Serono and Pfizer.Its product development pipeline includes

biological and chemical drugs formulated with

the Micropump, Medusa and other propri-

etary platforms.

MICROPUMP

The Micropump micro-encapsulation oral

drug delivery platform, for the formulation

and the controlled release of chemical drugs, is

designed to increase absorption time, particular-

ly for drugs only absorbed in the small intestine,

and to deliver the drug to specific sites in the

gastro-intestinal tract. Micropump allows tailor-

ing the exact kinetics required to optimise the

final product and offers the advantage of easily

and accurately mixing microparticles with dif-

ferent release kinetics, in different ratios, with

every individual particle performing indepen-

dently. A single Micropump formulation can be

presented in various dosage forms such as cap-

sule, tablet, sachet or oral suspensions without

affecting the release rate.

Flamel has developed US FDA- and

EMA-approved products and manufactures

Micropump-based microparticles.

TRIGGER LOCK

In addition to Micropump and LiquiTime,

Flamel has developed another oral drug delivery

technology, Trigger Lock, which provides

controlled release of narcotic and opioid analge-

sics while deterring tampering (particles cannot

be crushed to extract the active).

MEDUSA

Medusa is a proprietary injectable nanogel

platform for the formulation and/or the extended

release of a broad range of biologics (includingproteins, antibodies, peptides and vaccines)

and of small molecules. The nanogel has been

proven to be safe and biodegradable (DMF filed

with the FDA in February 2011).

Medusa enables the controlled delivery from

one day up to 14 days of non-modified drugs

that remain fully active (as opposed to protein

engineering or chemical modification approach-

es). It may be used to develop Biobetters with

potentially improved efficacy, reduced toxic-

ity and enhanced patient compliance. Several

Medusa-based products are at various clinical

stages of development. Flamels lead internal

Medusa-based product candidate IFN-a XL

(long-acting interferon alpha-2b) is currently

the subject of a Phase II trial in HCV patients.

DeliVax*, Medusas vaccine application,

permits the efficient formulation of vaccines.

These versatile drug delivery platforms may

be used to address threshold formulation prob-

lems such as poor solubility, aggregation and

instability for both chemical and biological

drugs. Flamels innovative delivery platforms

are used for the lifecycle management of mar-

keted products, including Biobetters, and the

development of new compounds with many

unique competitive advantages:

Improvement of drug characteristics such as

efficacy, bioavailability and pharmacokinetics

Improvement of the drug safety profile with a

noticeable diminution of peak dose concentra-

tions, which in turn allows administration of

higher effective doses and potentially greater

efficacy

Potential improvement of patient compliance

due to reduced side-effects and greater con-

venience

Protection of market position through patent

extension and/or product differentiation Extension of market to new indications and

new patient populations.

* pending trademarks

21

Figure 2: This graph illustrates the different zero-order release profiles achieved forLiquiTime-based formulations (easily tailored to obtain the appropriated targeted

product profile).

Prototype I

110

100

90

80

70

60

50

40

30

20

10

00 2

Time (hours)

%c

umutaliverelease

d

4 6 8 10 12 14 16 18 20 22 24

Prototype II


22/40


23/40


energy required to remove the volatile liquid

during the film casting process.

RELEASE LINERS

Significant research and expertise derived

from the transdermal arena has resulted in a

wide range of release liner technologies that

may be used as processing aids in the manu-

facture of OTFs. These materials are comprised

of a plastic film or paper substrate coated with

silicone or non-silicone chemistries for a clean

release of the film when appropriate in the con-

version process. By coating a compounded liq-

uid formulation to a continuous web of release

liner material, film manufacturers are able to

maintain the integrity of the OTF film product

throughout the manufacturing process because

this component provides added strength, sup-

port and environmental protection to wound

rolls of OTF film prior to finishing. Release lin-

ers can be incorporated strictly as a processing

aide that is removed in the film finishing stage,

or as seen in new product launches, this com-

ponent can remain affixed to the OTF to aid in

dispensing and administering the drug product.

ACTIVE INGREDIENTS

OTFs can integrate most available forms of

APIs, including micronised, granulated, salt,

and free-base forms. Both soluble and insoluble

drugs have been successfully compounded into

solutions, emulsions, or dispersions that have

subsequently resulted in the launches of the OTFproducts currently available in the market today.

Larger particle size compounds do present some

constraints in regards to the final OTFs thick-

ness, but in general, most APIs and nutritional

compound particle size distributions fall

Oral Drug Delivery May 2011 Lo Res

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